The following description of the background of this invention is provided only to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention.
Nucleotide analogues and prodrugs thereof have been extensively studied and described in the literature as potent antiviral and antitumor agents. In particular, various types, forms, uses, compositions, synthetic and analytical methods, drug delivery and other properties of nucleotide or nucleoside analogues including phosphonate nucleotide analogues and their orally active prodrugs, have been disclosed over the last 50 years in a plurality of scientific articles and patents such as, for example, U.S. Pat. No. 7,816,345 to Erion, et al. (Oct. 19, 2010); U.S. Pat. No. 7,803,788 to Becker, et al. (Sep. 28, 2010); U.S. Pat. No. 7,572,800 to Furman, et al. (Aug. 11, 2009); U.S. Pat. No. 7,439,350 to Bischofberger, et al. (Oct. 21, 2008); U.S. Pat. No. 7,390,791 to Becker, et al. (Jun. 24, 2008); U.S. Pat. No. 7,351,399 to Erion, et al. (Apr. 1, 2008); U.S. Pat. No. 7,214,668 to Reddy, et al. (May 8, 2007); U.S. Pat. No. 7,157,448 to Choi, et al. (Jan. 2, 2007); U.S. Pat. No. 7,115,592 to Balzarini, et al. (Oct. 3, 2006); U.S. Pat. No. 6,946,115 to Erion, et al. (Sep. 20, 2005); U.S. Pat. No. 6,727,059 to Derrien, et al. (Apr. 27, 2004); U.S. Pat. No. 6,653,296 to Holy, et al. (Nov. 25, 2003); U.S. Pat. No. 6,635,278 to Dahl, et al. (Oct. 21, 2003); U.S. Pat. No. 6,465,649 to Gutierrez, et al. (Oct. 15, 2002); U.S. Pat. No. 6,451,340 to Arimilli, et al. (Sep. 17, 2002); U.S. Pat. No. 6,432,631 to Cihlar (Aug. 13, 2002); U.S. Pat. No. 6,312,662 to Erion, et al. (Nov. 6, 2001); U.S. Pat. No. 6,225,460 to Bischofberger, et al. (May 1, 2001); U.S. Pat. No. 6,069,249 to Arimilli, et al. (May 30, 2000); U.S. Pat. No. 6,060,463 to Freeman (May 9, 2000); U.S. Pat. No. 6,057,305 to Holy, et al. (May 2, 2000); U.S. Pat. No. 6,043,230 to Arimilli, et al. (Mar. 28, 2000); U.S. Pat. No. 6,037,335 to Takashima, et al. (Mar. 14, 2000); U.S. Pat. No. 5,977,089 to Arimilli, et al. (Nov. 2, 1999); U.S. Pat. No. 5,977,061 to Holy, et al. (Nov. 2, 1999); U.S. Pat. No. 5,935,946 to Munger, Jr., et al. (Aug. 10, 1999); U.S. Pat. No. 5,922,695 to Arimilli, et al. (Jul. 13, 1999); U.S. Pat. No. 5,886,179 to Arimilli, et al. (Mar. 23, 1999); U.S. Pat. No. 5,877,166 to Reist, et al. (Mar. 2, 1999); U.S. Pat. No. 5,837,871 to Kim, et al. (Nov. 17, 1998); U.S. Pat. No. 5,817,647 to Casara, et al. (Oct. 6, 1998); U.S. Pat. No. 5,798,340 to Bischofberger, et al. (Aug. 25, 1998); U.S. Pat. No. 5,792,756 to Starrett, Jr., et al. (Aug. 11, 1998); U.S. Pat. No. 5,763,424 to Yuan (Jun. 9, 1998); U.S. Pat. No. 5,756,486 to Alexander, et al. (May 26, 1998); U.S. Pat. No. 5,717,095 to Arimilli, et al. (Feb. 10, 1998); U.S. Pat. No. 5,693,798 to Kim, et al. (Dec. 2, 1997); U.S. Pat. No. 5,686,629 to Bischofberger, et al. (Nov. 11, 1997); U.S. Pat. No. 5,663,159 to Starrett, Jr., et al. (Sep. 2, 1997); U.S. Pat. No. 5,659,023 to Alexander, et al. (Aug. 19, 1997); U.S. Pat. No. 5,656,745 to Bischofberger, et al. (Aug. 12, 1997); U.S. Pat. No. 5,650,510 to Webb, II, et al. (Jul. 22, 1997); U.S. Pat. No. 5,514,798 to Bischofberger, et al. (May 7, 1996); U.S. Pat. No. 5,476,938 to Vemishetti, et al. (Dec. 19, 1995); U.S. Pat. No. 5,470,857 to Borcherding, et al. (Nov. 28, 1995); U.S. Pat. No. 5,413,996 to Bodor (May 9, 1995); U.S. Pat. No. 5,302,585 to Yu, et al. (Apr. 12, 1994); U.S. Pat. No. 5,142,051 to Holy, et al. (Aug. 25, 1992); U.S. Pat. No. 5,130,427 to Alexander, et al. (Jul. 14, 1992); U.S. Pat. No. 5,055,458 to Bailey, et al. (Oct. 8, 1991); U.S. Pat. No. 4,968,788 to Farquhar (Nov. 6, 1990); U.S. Pat. No. 4,952,740 to Juge, et al. (Aug. 28, 1990); U.S. Pat. No. 4,816,570 to Farquhar (Mar. 28, 1989); U.S. Pat. No. 4,816,447 to Ashton, et al. (Mar. 28, 1989); U.S. Pat. No. 4,808,716 to Holy, et al. (Feb. 28, 1989); U.S. Pat. No. 4,724,233 to De Clercq, et al. (Feb. 9, 1988); U.S. Pat. No. 4,670,424 to MacCoss, et al. (Jun. 2, 1987); U.S. Pat. No. 4,659,825 to Holy, et al. (Apr. 21, 1987); U.S. Pat. No. 4,605,658 to Holy, et al. (Aug. 12, 1986); U.S. Pat. No. 4,590,269 to Prisbe, et al. (May 20, 1986); U.S. Pat. No. 4,347,360 to Ogilvie (Aug. 31, 1982); U.S. Pat. No. 4,287,188 to Schaeffer (Sep. 1, 1981); U.S. Pat. No. 4,230,708 to De Clercq, et al. (Oct. 28, 1980); and U.S. Pat. No. 3,929,840 to Christensen, et al. (Dec. 30, 1975). The above patents also include lists of many different references such as scientific papers, reviews and presentations relevant to nucleotide analogues. Such scientific articles along with the patents listed above are expressly incorporated herein by reference in their entirety.
Undoubtedly, regarding their antiviral activity against a broad spectrum of DNA and RNA viruses, one of the most important classes of known nucleotide analogues encountered in the literature is that of the phosphonate nucleotide analogues, especially that of the methoxy-phosphonate nucleotide analogues such as phosphinyl-methoxy-ethyl-adenine (i.e., PMEA or adefovir) and phosphinyl-methoxy-propyl-adenine (i.e., PMPA or tenofovir). However, due to their increased polarity attributed to the negative charges of the phosphorus atom, these compounds cannot be effective orally since they cannot efficiently penetrate the lipophilic membranes of the gastrointestinal tract and cells of various tissues. To address this problem, several investigators have reported prodrugs or intermediates of said compounds which use biologically reversible groups which are attached to these compounds via ether, ester, carbonate, amide or other types of physiologically hydrolysable bonds, thereby masking the polarity of the original entity and making it orally active since said protective groups can initially traverse the cell membranes and subsequently detach in physiologic conditions to reintroduce to the target cells the original effective medicament.
For example, certain prodrug diesters of PMEA and PMPA, such as 9-[2-[bis[(pivaloyloxy)-methoxy]phosphinyl]methoxy]ethyl]adenine, i.e., bis(POM)PMEA or adefovir dipivoxil, and 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]-methoxy]propyl]adenine, i.e., bis(POC)PMPA or tenofovir disoproxil, have been reported to exhibit significantly increased oral bioavailability as compared to their original compounds. In fact, Starrett, Jr., et al. in U.S. Pat. No. 5,663,159 report that the relative oral bioavailability (as compared to the corresponding absolute intravenous bioavailability) of adefovir is only 7.8 whereas that of its diesterified prodrug, adefovir dipivoxil, was found to be more than double, i.e., 17.0. Similarly, tenofovir disoproxil, the diesterified prodrug form of tenofovir, is significantly more bioavailable orally than the original drug, tenofovir. On the other hand, the monoesters of both adefovir and tenofovir, i.e., mono(POM)PMEA and mono(POC)PMPA, respectively, have been found to be significantly less orally bioavailable even as compared to their original, non-derivatized compounds. In fact, U.S. Pat. No. 5,663,159 discloses that the relative oral bioavailability of the monoester of adefovir is only 6.5, which is even less than that of the original compound adefovir (7.8) and, of course, that of its diester adefovir dipivoxil (17.0).
A constant and rather important drawback of the prodrug approach, however, has been the significant instability of the prepared prodrugs which tend to hydrolyze their ester linkages during synthesis, manufacturing and on storage, either stored by themselves or in pharmaceutical product formulations, thereby losing their protective masking groups and, consequently, exhibiting significantly reduced oral activity. To address this drawback, attempts have been made to introduce various types of crystal forms of such prodrugs in order to obtain reduced impurity levels during their synthesis and manufacturing and to improve the storage stability of the prepared prodrugs and their pharmaceutical compositions.
Arimilli, et al. in U.S. Pat. No. 6,451,340 disclose crystalline forms of adefovir dipivoxil in pharmaceutical compositions which, according to the inventors, are more manufacturable and stable than previous forms, e.g., the amorphous form, of the same drug. Using an ordinary composition of these adefovir dipivoxil crystals with other inactive ingredients, the assignee of the '340 patent, Gilead Sciences, Inc., has obtained an NDA approval for HEPSERA® (adefovir dipivoxil) tablets, 10 mg with an NDA application number of N021449. When HEPSERA® tablets were stored at a temperature of 60° C. and 75% relative humidity (“RH”), about 3.1% w/w of the less orally bioavailable monoester, mono(POM)PMEA, was formed in 5 days with respect to the original 10 mg quantity of the more bioavailable diester, adefovir dipivoxil, present initially in each HEPSERA® tablet. Furthermore, when the product of NDA #N021449 was stored at 40° C. and 75% RH, about 1.94%, 2.16% and 2.61% w/w of the less bioavailable monoester was formed in 1, 2 and 3 months, respectively.
Dahl, et al. in U.S. Pat. No. 6,635,278 assigned to the makers of HEPSERA® Tablets, Gilead Sciences, Inc., disclose the addition of an alkaline excipient such as magnesium or calcium carbonate to tablet compositions comprising crystalline adefovir dipivoxil and also containing optionally L-carnitine-L-tartrate. After storing these compositions for 6 to 8 days at 60° C. and 30% RH, the less bioavailable monoester was formed in weight percentages ranging from 2.8% to 4.4%. Furthermore, depending on the amount of desiccant included in the packaging of the prepared tablets, 96.6% to 97.3% w/w of adefovir dipivoxil remained in the tested preferred tablet compositions (i.e., 2.7% to 3.4% w/w degradation) after storage at 60° C. and 75% RH for 1 week, whereas 97.6% and 97.8% w/w of the drug remained in the most preferred composition (i.e., 2.2% and 2.4% w/w degradation) after storage at 40° C. and 75% RH for 3 months.
In addition, Munger, Jr., et al. in U.S. Pat. No. 5,935,946 also assigned to Gilead Sciences, Inc., disclose a crystalline form of the diester bis(POC)PMPA (or tenofovir disoproxil) in which the crystals are made of tenofovir disoproxil fumarate complexes each comprising one part of tenofovir disoproxil and one part of fumaric acid. The disclosed crystals are claimed not only to increase the stability as compared to the original diester prodrug, tenofovir disoproxil, but also, as compared to another crystalline salt, namely, tenofovir disoproxil citrate. After storing the materials for 3 days at 60° C. and 75% RH, the less bioavailable monoester, mono(POC)—PMPA, was formed in weight percentages of 3.1% and 58.9% from the tenofovir disoproxil fumarate and citrate crystals, respectively. On the other hand, storage of the materials at 40° C. and 75% RH resulted in formation of 1.9% and 2.9% of the less bioavailable monoester in 1 and 2 months, respectively, from the tenofovir disoproxil fumarate material, whereas 7.1% and 22.4% w/w of the monoester was formed in 1 and 2 months, respectively, from the tenofovir disoproxil citrate material. It should be also mentioned that during the preparation of these crystalline materials, it is reported that 1% of the undesirable and less bioavailable monoester had been already formed soon after production of both of these materials.
Another possible disadvantage of the prodrug approach could also be a rather high rate of degradation and chemical instability of prepared prodrugs when exposed to aqueous environments, namely, prodrugs suspended or dissolved in gastric or intestinal fluids or absorbed in the blood at a molecular state. Depending on the synthesis of the prodrug and/or the manufacturing or storage of the prodrug, or of the finished product containing such prodrug, its particular or molecular dispersions in aqueous environments may exhibit unacceptably fast drug destabilization rates resulting most probably from the hydrolysis of their ester linkages, thereby possibly leading to high levels of orally inactive degradation products or other impurities of such prodrug. In fact, based on recent studies conducted by the inventors named in the present application, it was found that the crystalline form of Adefovir Dipivoxil contained in the commercial brand product HEPSERA® hydrolyzes in-situ to as much as 11.6% by weight of its significantly less orally bioavailable monoester form when a HEPSERA® 10 mg tablet is dissolved in 250 milliliters of purified water maintained at 37° C. and stirred at 60 rpm for one hour. To date, no significant attempts have been made to address this type of in-situ aqueous solution degradation of such prodrugs.
In view of the foregoing, existing methods, forms and compositions of orally active nucleotide analogue prodrugs do not yield products: (i) containing insignificant amounts of undesirable and less orally bioavailable impurities, (ii) exhibiting high storage stability whether stored alone, in combination or as finished products, and (iii) demonstrating reduced in-situ degradation while being suspended or dissolved in aqueous environments. As discussed, it appears that the available/disclosed past and present forms and compositions of such orally active prodrugs of nucleotide analogues, in their so far best performance mode, degrade to yield more than 2.2% w/w of their significantly less orally bioavailable impurity after storage at 40° C. and 75% RH for 3 months. In fact, based on this quite pronounced destabilization potential of such analogue prodrugs, it is highly possible that there might have been instances wherein promising orally active nucleotide analogue prodrugs have been rejected from clinical trials due to their manufacturing and storage instability resulting from inadequate stabilization techniques.
The foregoing shows that there exists an unmet need to form compositions of orally active nucleotide analogues and orally active nucleotide analogue prodrugs, which would not only present high stability properties during their storage by degrading to significantly reduced amounts of their less orally bioavailable impurities as compared to current forms and compositions, but also, would yield significantly lower initial quantities of such undesirable impurities soon after their manufacturing, and furthermore, would minimally degrade in-situ to their less orally bioavailable impurities when suspended or dissolved in aqueous environments such as blood and gastrointestinal fluids.